Work of the research groups listed below at the Whitehead Institute for Biomedical Research (WIBR) is a focused on the use of molecular biology and genetics to analyze complex biological problems in developmental biology and genetics, mammalian genetics, control of cell growth, gene therapy, replication of human pathogens, signal transduction pathways and the structure of biological molecules. With the exception of one small research group using computational processes to analyze molecular structure, all the research groups at the WIBR rely to greater or lesser extents on the analysis and manipulation of DNA molecules in order to identify, analyze and dissect the genes governing the biological systems of interest to them. The use of DNA sequencing has figured prominently in these analyses and manipulations. New genes are frequently being isolated and analyzed in detail by sequence analysis. Even more important, however, are the years of experiments that follow during which isolated genes are dissected, reconfigured, perturbed by site-directed mutagenesis, and then functionally studied. This re-engineering of isolated DNA segments makes intensive use of DNA sequencing to monitor continually the progress of the successive steps-involved in the reconstruction and reconfiguring of gene segments. Indeed, the progress of these manipulations is often determined by the rapidity with which reconstructed DNA segments can be sequenced in order to monitor success of the most recent manipulation. All this work has been performed manually since the founding of the WIBR in its various laboratories with the exception of a recently established automatic sequencing facility that is owned by the Human Genome Project. (Use of this facility has been and will be limited exclusively to those working directly on this project. The existing equipment of the Human Genome Project will shortly be removed from its current WIBR premises to a new, off-site facility.) During the past decade, automated sequencing technology has been developed to the stage that it is practical and results in very substantial increases in laboratory productivity. The use of automated sequencing instrumentation speeds up a factor of 5-10 the rate with which sequencing can be carried, and it is anticipated that the investment made in this equipment will be recovered in terms of improved productivity of the WIBR's NIH-sponsored research programs within 2-3 years' time. Thus, the experience provided by the Human Genome Project's WTBR facility (see above) informs us that with such equipment, we should be able to sequence nearly 500 templates per week (or approximately 15,000 nucleotides per week) with this instrument.